No abstract

A robust preclinical disease model is a primary requirement to understand the underlying mechanisms, signaling pathways, and drug screening for human diseases. Although various preclinical models are available for several diseases, clinical models for Alzheimer’s disease (AD) remain underdeveloped and inaccurate. The pathophysiology of AD mainly includes the presence of amyloid plaques and neurofibrillary tangles (NFT). Furthermore, neuroinflammation and free radical generation also contribute to AD. Currently, there is a wide gap in scientific approaches to preventing AD progression. Most of the available drugs are limited to symptomatic relief and improve deteriorating cognitive functions. To mimic the pathogenesis of human AD, animal models like 3XTg-AD and 5XFAD are the primarily used mice models in AD therapeutics. Animal models for AD include intracerebroventricular-streptozotocin (ICV-STZ), amyloid beta-induced, colchicine-induced, etc., focusing on parameters such as cognitive decline and dementia. Unfortunately, the translational rate of the potential drug candidates in clinical trials is poor due to limitations in imitating human AD pathology in animal models. Therefore, the available preclinical models possess a gap in AD modeling. This paper presents an outline that critically assesses the applicability and limitations of the current approaches in disease modeling for AD. Also, we attempted to provide key suggestions for the best-fit model to evaluate potential therapies, which might improve therapy translation from preclinical studies to patients with AD.

No abstract

As acetylcholinesterase (AChE) plays a crucial role in advancing Alzheimer’s disease (AD), its inhibition is a promising approach for treating AD. Sulindac is an NSAID of the aryl alkanoic acid class, consisting of a indene moiety, which showed neuroprotective behavior in recent studies. In this study, newer Indene analogs were synthesized and evaluated for their in vitro AChE inhibition. Additionally, compared with donepezil as the standard drug, these Indene analogs were accessed for their cell line-based toxicity study on SH-SY5Y cell line. The molecule SD-30, having hydrogen bond donor (HBD) at para-position, showed maximum AChE inhibition potential (IC50 13.86 ± 0.163 µM) in the indene series. Further, the SD-30 showed maximum BuChE inhibition potential (IC50 = 48.55 ± 0.136 µM) with a selectivity ratio of 3.50 and reasonable antioxidant properties compared to ascorbic acid (using DPPH assay). SD-30 (at a dose level: of 10 µM, 20 µM) effectively inhibited AChE-induced Aβ aggregation and showed no significant toxicity up to 30 mM against SH-SY5Y cell lines.